The present invention relates to novel amine derivatives exhibiting excellent antifungal activity.
These days, an increased number of victims suffer from superficial mycosis, led by athlete""s foot. However, no reliable therapy or remedy therefor has yet been established. Thus, superficial mycosis is counted as a disease that has not yet been overcome by modern medicine. Extensive efforts have heretofore been made in an attempt toward discovery of remedies therefor, and numerous compounds have been screened for their potential antifungal action. Regrettably, not a few compounds that have been confirmed to exhibit activity in vitro or in animals are found unsatisfactory when used in actual clinical settings, and therefore, only a limited number of compounds yield satisfactory results.
In view of the foregoing, an object of the present invention is to provide novel compounds exhibiting excellent antifungal activity.
Under the above-described situation, the present inventors have performed extensive studies, and have found that amine derivatives represented by the below-described formula (1) exhibit excellent antifungal activity, leading to completion of the invention.
Accordingly, the present invention provides an amine derivative of formula (1): 
(wherein R1 represents a C1-C4 linear, branched, or cyclic alkyl group; R2 represents a group represented by (i), (ii), or (iii); 
R3 represents a C1-C3 linear, branched, or cyclic alkyl group, a hydroxylated C1-C5 linear, branched, or cyclic alkyl group, a C1-C5 linear, branched, or cyclic acyl group, a C2-C5 linear, branched, or cyclic alkenyl group, or a halogen atom;
R3 in the number of m may be identical to or different from one another; k, l, and m are each an integer of 1 to 4; and
R4 represents a C1-C4 linear alkyl group or phenyl group) and a salt thereof.
The present invention also provides an antifungal agent comprising the amine derivative of formula (1) or a salt thereof.
The present invention also provides an antifungal composition comprising the amine derivative of formula (1) or a salt thereof.
The present invention also provides a drug comprising, as an active ingredient, the amine derivative of formula (1) or a salt thereof.
The present invention also provides a pharmaceutical composition comprising the amine derivative of formula (1) or a salt thereof, and a pharmaceutically acceptable carrier.
The present invention also provides use, as a drug, of the amine derivative of formula (1) or a salt thereof.
The present invention also provides a method for the treatment of a fungal infectious disease through administration of the amine derivative of formula (1) or a salt thereof to a patient in need thereof.
The amine derivatives according to the present invention are represented by the aforementioned formula (1). In the formula, examples of R1 representing a C1-C4 linear, branched, or cyclic alkyl group include, but are not limited to, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, and a cyclobutyl group. Of these groups, C1-C3 groups; particularly, methyl, ethyl, isopropyl, and cyclopropyl groups are preferred.
R2 is a group represented by (i), (ii), or (iii), with (i) and (ii) being particularly preferred.
Of the groups represented by R3, examples of C1-C3 linear, branched, or cyclic alkyl groups include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a cyclopropyl group. Of these groups, a methyl group is preferred.
Examples of preferred hydroxylated C1-C5 linear, branched, or cyclic alkyl groups include a 1-hydroxy-1-methyl ethyl group, and a 1,2-dimethyl-1-hydroxypropyl group.
Examples of the C1-C5 linear, branched, or cyclic acyl groups include a formyl group and a C2-C5 alkanoyl group. Of these groups, a formyl group, an acetyl group, and a propionyl group are preferred.
Examples of preferred ones of the C2-C5 linear, branched, or cyclic alkenyl groups include a vinyl group, an isopropenyl group, a 2-methyl-1-propenyl group, a 1-ethylvinyl group, a 1-methyl-1-propenyl group, and a 1-isopropylvinyl group.
Examples of the halogen atoms include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
Preferred examples of R3 include, among others, a methyl group, a 1-hydroxy-1-methylethyl group, a 1,2-dimethyl-1-hydroxypropyl group, a 1-hydroxypropyl group, a formyl group, an acetyl group, a propionyl group, a vinyl group, an isopropenyl group, a 2-methyl-1-propenyl group, a 1-ethylvinyl group, a 1-methyl-1-propenyl group, a 1-isopropyl vinyl group, a fluorine atom, and a bromine atom.
R3 groups appearing in the number of m may be identical to or different from one another.
Of the R3 groups, at least one group is preferably a C2-C5 linear, branched, or cyclic alkenyl group; particularly, a vinyl group, an isopropenyl group, a 2-methyl-1-propenyl group, a 1-ethylvinyl group, a 1-methylpropenyl group, or a 1-isopropylvinyl group.
k, l, and m are each independently an integer of 1 to 4. Preferably, k is 1, l is 1, and m is 1-3.
R4 represents a C1-C4 linear alkyl group or phenyl group. Particularly, a methyl group and a phenyl group are preferred.
Specific examples of preferred amine derivatives of formula (1) include the following.
Trans-3xe2x80x2-[N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylaminomethyl]acetophenone,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-isopropenylbenzyl)amine,
Cis-3xe2x80x2-[N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylaminomethyl]acetophenone,
Cis-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-isopropenylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-bromobenzyl)amine,
Trans-3-[N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylaminomethyl]benzaldehyde,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-vinylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-[3-(2-methyl-1-propenyl)benzyl]amine,
Trans-3xe2x80x2-[N-cyclopropyl-N-(6,6-dimethyl-2-hepten-4-ynyl)aminomethyl]acetophenone,
Trans-N-cyclopropyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-(3-isopropenylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-bromo-5-methylbenzyl)amine,
2-[3-{N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylaminomethyl}-5-methylphenyl]-2-propanol,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-isopropenyl-5-methylbenzyl)amine,
2-[3-{N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylaminomethyl}phenyl]-3-methyl-2-butanol,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-[3-(1-isopropylvinyl)benzyl]amine,
Trans-3xe2x80x2-[N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylaminomethyl]propiophenone,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-[3-(1-ethylvinyl)benzyl]amine,
Trans,cis-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-[3-(1-methyl-1-propenyl)benzyl]amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-bromo-4-fluorobenzyl)amine,
Trans-2-[2-fluoro-5-{N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylaminomethyl}phenyl]-2-propanol,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(4-fluoro-3-isopropenylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(5-bromo-2-methylbenzyl)amine,
Trans-2-[3-{N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylaminomethyl}-4-methylphenyl]-2-propanol,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(5-isopropenyl-2-methylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(2-bromobenzyl)amine,
2-[3-{N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylaminomethyl}phenyl]-2-propanol,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(2-isopropenylbenzyl)amine,
Trans-3xe2x80x2-[N-(6,6-dimethyl-2-hepten-4-ynyl)-N-isopropylaminomethyl]acetophenone,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-isopropyl-(3-isopropenylbenzyl)amine,
Trans-3xe2x80x2-[N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethylaminomethyl]acetophenone,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-(3-isopropenylbenzyl)amine,
3xe2x80x2-(N-cinnamyl-N-methylaminomethyl)acetophenone,
N-cinnamyl-N-methyl-(3-isopropenylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-bromo-2-methylbenzyl)amine,
Trans-2-[3-{N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylaminomethyl}-2-methylphenyl-2-propanol,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-isopropenyl-2-methylbenzyl)amine,
Trans-N-(6,6-dimetnyl-2-hepten-4-ynyl)-N-methyl-(2-bromo-6-methylbenzyl)amine,
Trans-2-[2-{N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylaminomethyl}-3-methylphenyl]-2-propanol,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(2-isopropenyl-6-methylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(5-bromo-2-fluorobenzyl)amine,
Trans-2-[3-{N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylaminomethyl)-4-fluorophenyl]-2-propanol,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(2-fluoro-5-isopropenylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-bromo-5-fluorobenzyl)amine,
Trans-2-[3-{N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylaminomethyl)-5-fluorophenyl]-2-propanol,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-fluoro-5-isopropenylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3,5-dibromobenzyl)amine,
Trans-2-[5-bromo-3-{N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylaminomethyl}phenyl]-2-propanol,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-bromo-5-isopropenylbenzyl)amine,
Trans-2-[3-{N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylaminomethyl}-5-isopropenylphenyl]-2-propanol,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3,5-bisisopropenylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-bromo-4-methylbenzyl)amine,
Trans-2-[5-{N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylamionomethyl}-2-methylphenyl]-2-propanol,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-isopropenyl-4-methylbenzyl)amine,
3xe2x80x2-[N-(4-tert-butylbenzyl)-N-methylaminomethyl]acetophenone,
N-(4-tert-butylbenzyl)-N-methyl-(3-isopropenylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-methyl-(3-bromobenzyl)amine,
3-[N-(4-tert-butylbenzyl)-N-methylaminomethyl]benzaldehyde,
N-(4-tert-butylbenzyl)-N-methyl-(3-vinylbenzyl)amine,
3xe2x80x2-[N-(4-tert-butylbenzyl)-N-cyalopropylaminomethyl]acetophenone,
N-(4-tert-butylbenzyl)-N-cyclopropyl-(3-isopropenylbenzyl)amine,
N-(4-tert-butylbenyzyl)-N-methyl-(3-bromo-5-methylbenzyl)amine,
2-[3-{-(4-tert-butylbenzyl)-N-methylaminomethyl}-5-methylphenyl]-2-propanol,
N-(4-tert-butylbenzyl)-N-methyl-(3-isopropenyl-5-methylbenzyl)amine,
2-[3-{N-(4-tert-butylbenzyl)-N-methylaminomethyl}phenyl]-3-methyl-2-butanol,
N-(4-tert-butylbenzyl)-N-methyl-[3-(1-isopropylvinyl)benzyl]amine,
1-[3-{N-(4-tert-butylbenzyl)-N-methylaminomethyl}phenyl]-1-propanol,
3xe2x80x2-[N-(4-tert-butylbenzyl)-N-methylaminomethyl]propiophenone,
N-(4-tert-butylbenzyl)-N-methyl-[3-(1-ethylvinyl)benzyl]amine,
Cis-N-(4-tert-butylbenzyl)-N-methyl-[3-(1-methyl-1-propenyl)benzyl]amine,
N-(4-tert-butylbenzyl)-N-methyl-(3-bromo-5-fluorobenzyl)amine,
2-[3-{N-(4-tert-butylbenzyl)-N-methylaminomethyl}-5-fluorophenyl]-2-butanol,
N-(4-tert-butylbenzyl)-N-methyl-(3-fluoro-5-isopropenylbenzyl)amine,
3xe2x80x2-[N-4-(1-methyl-1-phenylethyl)benzyl-N-methylaminomethyl]acetophenone,
N-methyl-N-[4-(1-methyl-1-phenylethyl)benzyl]-(3-isopropenylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-methyl-(2-bromobenzyl)amine,
2-[3-{N-(4-tert-butylbenzyl)-N-methylaminomethyl}phenyl]-2-propanol,
N-(4-tert-butylbenzyl)-N-methyl-(2-isopropenylbenzyl)amine,
3xe2x80x2-[N-(4-tert-butylbenzyl)-N-isopropylaminomethyl]acetophenone,
N-(4-tert-butylbenzyl)-N-isopropyl-(3-isopropenylbenzyl)amine,
3xe2x80x2-[N-(4-tert-butylbenzyl)-N-ethylaminomethyl]acetophenone,
N-(4-tert-butylbenzyl)-N-ethyl-(3-isopropenylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-methyl-(3-bromo-2-methylbenzyl)amine,
2-[3-{N-(4-tert-butylbenzyl)-N-methylaminomethyl}-2-methylphenyl]-2-propanol,
N-(4-tert-butylbenzyl)-N-methyl-(3-isopropenyl-2-methylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-methyl-(2-bromo-6-methylbenzyl)amine,
2-[2-{N-(4-tert-butylbenzyl)-N-methylaminomethyl}-3-methylphenyl]-2-propanol,
N-(4-tert-butylbenzyl)-N-methyl-(2-isopropenyl-6-methylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-methyl-(3-bromo-4-methylbenzyl)amine,
2-[5-{N-(4-tert-butylbenzyl)-N-methylaminomethyl}-2-methylphenyl]-2-propanol,
N-(4-tert-butylbenzyl)-N-methyl-(3-isopropenyl-4-methylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-methyl-(3-bromo-4-fluorobenzyl)amine,
2-[5-{N-(4-tert-butylbenzyl)-N-methylaminomethyl}-2-fluorophenyl]-2-propanol,
N-(4-tert-butylbenzyl)-N-methyl-(4-fluoro-3-isopropenylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-methyl-(5-bromo-2-fluorobenzyl)amine,
2-[3-{N-(4-tert-butylbenzyl)-N-methylaminomethyl}-4-fluorophenyl]-2-propanol,
N-(4-tert-butylbenzyl)-N-methyl-(2-fluoro-5-isopropenylbenzyl)amine,
N-(3-bromo-5-methylbenzyl)-N-methyl-[4-(1-methyl-1-phenylethyl)benzyl]amine,
2-[3-methyl-5-[N-methyl-N-{4-(1-methyl-1-phenylethyl)benzyl}aminomethyl]phenyl]-2-propanol,
N-methyl-N-[4-(1-methyl-1-phenylethyl)benzyl]-(3-isopropenyl-5-methylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-methyl-(3,5-dibromobenzyl)amine,
2-[3-bromo-5-{N-(4-tert-butylbenzyl)-N-methylaminomethyl}phenyl]-2-propanol,
N-(4-tert-butylbenzyl)-N-methyl-(3-bromo-5-isopropenylbenzyl)amine,
2-[3-isopropenyl-5-{N-(4-tert-butylbenzyl)-N-methylaminomethyl}phenyl]-2-propanol, and
N-(4-tert-butylbenzyl)-N-methyl-(3,5-bisisopropenylbenzyl)amine.
Of the above-listed compounds, the following compounds are more preferred:
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-isopropenylbenzyl)amine,
Cis-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-isopropenylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-vinylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-[3-(2-methyl-1-propenyl)benzyl]amine,
Trans-N-cyclopropyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-(3-isopropenylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-isopropenyl-5-methylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-[3-(1-isopropylvinyl)benzyl]amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-[3-(1-ethylvinyl)benzyl]amine,
Trans,cis-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-[3-(1-methyl-1-propenyl)benzyl]amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(4-fluoro-3-isopropenylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(5-isopropenyl-2-methylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(2-isopropenylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-isopropyl-(3-isopropenylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-(3-isopropenylbenzyl)amine,
N-cinnamyl-N-methyl-(3-isopropenylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-isopropenyl-2-methylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(2-isopropenyl-6-methylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(2-fluoro-5-isopropenylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-fluoro-5-isopropenylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-bromo-5-isopropenylbenzyl)amine,
Trans-2-[3-{N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylaminomethyl}-5-isopropenylphenyl]-2-propanol,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3,5-bisisopropenylbenzyl)amine,
Trans-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-(3-isopropenyl-4-methylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-methyl-(3-isopropenylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-methyl-(3-vinylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-cyclopropyl-(3-isopropenylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-methyl-(3-isopropenyl-5-methylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-methyl-[3-(1-isopropylvinyl)benzyl]amine,
N-(4-tert-butylbenzyl)-N-methyl-[3-(1-ethylvinyl)benzyl]amine,
Cis-N-(4-tert-butylbenzyl)-N-methyl-[3-(1-methyl-1-propenyl)benzyl]amine,
N-(4-tert-butylbenzyl)-N-methyl-(3-fluoro-5-isopropenylbenzyl)amine,
N-methyl-N-[4-(1-methyl-1-phenylethyl)benzyl]-(3-isopropenylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-methyl-(2-isopropenylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-isopropyl-(3-isopropenylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-ethyl-(3-isopropenylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-methyl-(3-isopropenyl-2-methylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-methyl-(2-isopropenyl-6-methylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-methyl-(3-isopropenyl-4-methylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-methyl-(4-fluoro-3-isopropenylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-methyl-(2-fluoro-5-isopropenylbenzyl)amine,
N-methyl-N-[4-(1-methyl-1-phenylethyl)benzyl]-(3-isopropenyl-5-methylbenzyl)amine,
N-(4-tert-butylbenzyl)-N-methyl-(3-bromo-5-isopropenylbenzyl)amine,
2-[3-isopropenyl-5-(N-(4-tert-butylbenzyl)-N-methylaminomethyl}phenyl]-2-propanol, and
N-(4-tert-butylbenzyl)-N-methyl-(3,5-bisisopropenylbenzyl)amine.
Salts which may be used in the present invention are not particularly limited, so long as they are physiologically acceptable. Preferred examples of such salts include salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; salts of organic acids such as citric acid, oxalic acid, fumaric acid, maleic acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, and corbonic acid. Of these salts, hydrochloric acid salts are particularly preferred. These salts can be obtained from an amine derivative of formula (1) and an acid according to a customary method; for example, an amine derivative of formula (1) and an acid are mixed in a polar or non-polar solvent.
The compounds of formula (1) according to the present invention encompass solvates, such as hydrates.
The compounds of formula (1) according to the present invention may be prepared through, for example, the following reaction scheme (I) or (II). 
(wherein R1, R2, R3, k, l, and m have the same meanings, and X represents a halogen atom.)
Briefly, a secondary amine derivative (2) or a salt thereof and a halide (3) are subjected to a condensation reaction (Process 1), or alternatively, a halide (4) and a secondary amine derivative (5) or a salt thereof are subjected to a condensation reaction (Process 11), to thereby yield an amine derivative (1) of the present invention. The condensation reactions may be performed through use of a condensing agent in the presence of a solvent.
In either process (I) or (II), the ratio of the raw materials; i.e., the ratio of the secondary amine derivative to the halide, is generally preferably from 0.1 to 10.0 by mol, and particularly preferably from 1.0 to 2.5 by mol. The condensing agent used in the reaction is a tertiary organic amine or an inorganic base. Specifically, mention may be given of, among others, triethylamine, N,N-diisopropylethylamine, anhydrous potassium carbonate, and anhydrous sodium carbonate. Any of these condensing agents is generally used in an amount of 0.1 to 30.0 mol, preferably from 2.0 to 5.0 mol, on the basis of the entirety of the raw materials.
The solvent to be used in the reaction is not particularly limited so long as it is a non-aqueous solvent that can dissolve therein the two raw materials. A specific example is N,N-dimethylformamide. The amount of the solvent is preferably 5 to 100 times the amount of the reactive starting materials. The solvent may be used singly or in combination of two or more species. Selection of the solvent is performed in accordance with physical properties of the starting compound and condensing agent employed.
The reaction temperature may be any temperature between room temperature and the boiling point of the solvent. Preferably, the reaction temperature is room temperature. The reaction time may vary depending on conditions, and generally, it requires 10 minutes to 30 days. Post-treatment and purification may be performed according to customary methods; for example, quenching with water, extraction with a solvent, column chromatography, and recrystallization, which may be combined appropriately.
The compounds of formula (1) according to the present invention may be produced through, for example, the following reaction scheme III or IV. 
(wherein R1, R2, R3, k, l, and m have the same meanings.)
Briefly, a secondary amine derivative (2) or a salt thereof and an aldehyde derivative (6) are subjected to a condensation reaction (Process III), or alternatively, an aldehyde derivative (7) and a secondary amine derivative (5) or a salt thereof are subjected to a condensation reaction (Process IV), to thereby yield an amine derivative (1) of the present invention. The condensation reactions may be performed by causing a reaction between an amine moiety and an aldehyde moiety, and then forming a tertiary amine moiety through use of a reducing agent.
In either process (III) or (IV), the ratio of the raw materials; i.e., the ratio of the secondary amine derivative to the aldehyde derivative, is generally preferably from 0.1 to 10.0 by mol, and particularly preferably from 1.0 to 2.5 by mol.
The solvent to be used in the reaction is not particularly limited so long as it is a non-aqueous solvent that can dissolve therein the two raw materials. A specific example is methanol. The amount of the solvent is preferably 5 to 100 times the amount of the reactive starting materials. The solvent may be used singly or in combination of two or more species. Selection of the solvent is performed in accordance with physical properties of the starting compound and condensing agent employed.
First, in order to carry out the reaction between a secondary amine derivative and an aldehyde derivative, the reaction system is preferably turned to basic by use of an inorganic base such as potassium hydroxide or sodium hydroxide, or an organic base such as triethylamine or N,N-diisopropylethylamine. The reaction temperature may be any temperature between room temperature and the boiling point of the solvent. Preferably, the reaction temperature is room temperature. The reaction time may vary depending on the conditions, and generally, it requires 10 minutes to 30 days.
Next, in order to perform a reaction with a reducing agent, the reducing agent is caused to react as is without isolating the intermediate obtained from the two raw materials. Examples of the reducing agent which may be used include sodium cyanoborohydride and sodium borohydride. The amount of the reducing agent is determined in accordance with the amount of the raw materials employed. The time during which the reducing agent is reacted may vary depending on the conditions, and generally, it requires 10 minutes to 30 days. Post-treatment and purification may be performed according to customary methods; for example, quenching with water, extraction with a solvent, column chromatography, and recrystallization, which may be combined appropriately.
When substituent conversion is performed before or after any of Processes I to IV, other amine derivatives of formula (1) may be obtained. Specific examples of such substituent conversion include:
halogenation by use of N-bromosuccinimide, phosphorus tribromide, etc.;
conversion of a primary amino group to a secondary amino group by use of an alkyl halide;
conversion of a carbonyl group to a Cxe2x95x90C double bond through the Wittig reaction, such as from formyl to vinyl, formyl to 2-methyl-1-propenyl, acetyl to isopropenyl, acetyl to 1-methyl-1-propenyl, propionyl to 1-ethylvinyl, etc.;
halogen-metal exchange reaction between, for example, an aromatic halogen atom and n-butyl lithium, and subsequent reaction with an acylation source such as N,N-dimethylformamide for conversion into an acyl group, such as a formyl group;
halogen-metal exchange reaction between, for example, an aromatic halogen atom and n-butyl lithium, and subsequent reaction with a ketone such as acetone or 3-methyl-2-butanone for conversion into a 1-hydroxy-1-methylethyl group, a 1,2-dimethyl-1-hydroxypropyl group, etc.; and
creation of a Cxe2x95x90C double bond characterized by dehydration reaction by use of phosphorus oxychloride; e.g., conversion from a 1-hydroxy-1-methylethyl group into an isopropenyl group, from a 1,2-dimethyl-1-hydroxypropyl group to a 1-isopropylvinyl group.
The amine derivatives of the formula (1) according to the present invention or salts thereof exhibit excellent antifungal activity, and thus are very useful in the manufacture of antifungal compositions, drugs containing the derivatives, and so on.
The antifungal compositions of the present invention can be produced through incorporation of one or more species of the amine derivatives (1) or salts thereof. No particular limitation is imposed on the type of the compositions, so long as they are compositions known to contain antifungal agents. Examples of such compositions include pharmaceutical compositions such as topical skin agents, and external agents for washing or sterilization; clothing such as socks and underwear; and plastics such as toothbrushes and ball-point pens. Of these, topical skin agents are most preferred. The amine derivatives (1) of the present invention or salts thereof may be formulated into a composition through known techniques. For example, when pharmaceutical compositions are to be prepared, a compound of the present invention may be emulsified or solubilized along with other ingredients, or alternatively, the compound may be admixed with powder ingredients and then granulated. When clothing are produced, the compound may be melt-kneaded during the fiber production step, followed by spinning, or alternatively, clothing may be impregnated with the compound. When plastic products are produced, incorporation of the compound through melt-kneading is preferred. Also, wood or similar materials may be impregnated with the compound for the purpose of anti-molding.
Compositions of the present invention may include, other than the amine derivatives (1) or salts thereof, arbitrary ingredients which are generally contained in such compositions, as needed. The arbitrary ingredients are not particularly limited, and when pharmaceutical compositions are prepared, coloring agents, sweetening/flavoring agents, binders, disintegrators, coating agents, stabilizers, pH regulators, sugar coaters, emulsification/dispersing/solubilizing agents, etc. may be incorporated. Of these, when topical skin agents are prepared, the following may be incorporated: hydrocarbons such as liquid paraffin and VASELINE; esters such as spermaceti and beeswax; triglycerides such as olive oil and beef tallow; higher alcohols such as cetanol and oleyl alcohol; fatty acids such as stearic acid and oleic acid; polyols such as propylene glycol and glycerol; nonionic surfactants; anionic surfactants; cationic surfactants; and thickeners. When clothing and plastic products are produced, plasticizers, cross-linking agents, colorants, antioxidants, and UV absorbers may be incorporated. The amount of the amine derivatives or salts thereof to be incorporated into the compositions of the present invention is not particularly limited, and is preferably 0.001-20 wt. %, more preferably 0.01-15 wt. %, most preferably 0.1-10 wt. %.